Indications
Enzalutamide is a therapeutic agent primarily indicated for the management of various forms of prostate cancer. It is prescribed for patients with castration-resistant prostate cancer (CRPC), as well as those with metastatic and non-metastatic castration-sensitive prostate cancer (mCSPC and nmCSPC) who exhibit high-risk biochemical recurrence. Enzalutamide is also utilized in combination with talazoparib for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
Pharmacodynamics
Enzalutamide functions as a second-generation antiandrogen, effectively inhibiting the activity of androgens and androgen receptors (AR) in prostate cancer cells. The relationship between AR activity and prostate cancer progression underscores the necessity for androgen deprivation therapy (ADT). Despite ADT's initial effectiveness, resistance often develops within 2-3 years due to various mutations, such as constitutively active AR mutations, AR overexpression, and alterations in AR splicing variants. Enzalutamide is strategically designed to target these mutations. In vitro studies have demonstrated that enzalutamide can significantly suppress cell growth and induce apoptosis in human prostate cancer cell lines, whereas other antiandrogens like bicalutamide did not show similar effectiveness. Clinical trials have also revealed that enzalutamide can reduce serum PSA levels in patients for at least 12 weeks and decrease the risk of death by 37% compared to placebo, despite the potential for resistance development.
Absorption
Following administration, enzalutamide is rapidly absorbed, with a median time to maximum concentration (Tmax) of 1 hour for capsules and approximately 2 hours for tablets. The medication reaches a steady state by day 28, with an accumulation of the area under the curve (AUC) approximately 8.3 times that of a single dose. At steady state, the mean maximum concentration (Cmax) for enzalutamide and its active metabolite N-desmethyl enzalutamide are 16.6 µg/mL and 12.7 µg/mL, respectively. The mean minimum concentrations (Cmin) observed are 11.4 µg/mL and 13.0 µg/mL, respectively.
Metabolism
Enzalutamide metabolism primarily involves the cytochrome P450 enzymes CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the conversion of enzalutamide to its active metabolite, N-desmethyl enzalutamide. Carboxylesterase 1 further metabolizes both N-desmethyl enzalutamide and enzalutamide into an inactive carboxylic acid metabolite, thereby influencing the pharmacokinetic profile and activity of the drug.
Mechanism of Action
Enzalutamide functions as a potent competitive inhibitor of the androgen receptor (AR), effectively impeding the androgen signaling pathway without displaying significant agonistic activity. This is achieved through a threefold mechanism: preventing androgen binding to the AR, obstructing the translocation of the androgen receptor into the nucleus, and hindering the interaction with chromosomal DNA, which otherwise leads to the upregulation of oncogenes. Notably, enzalutamide demonstrates a binding affinity to the AR that is 5 to 8 times greater than that of first-generation antiandrogens like bicalutamide, while maintaining only 2-3 fold reduced affinity compared to dihydrotestosterone, the natural ligand. Molecular docking studies have revealed that enzalutamide engages the ligand-binding domain of the androgen receptor in a manner distinct from bicalutamide.
